Lisdexamfetamine dimesylate is approved and marketed in the United States for the treatment of attention-deficit hyperactivity disorder in pediatric patients. The active compound lisdexamfetamine contains D-amphetamine covalently linked to the essential amino acid L-lysine. Controlled release of D-amphetamine, a psychostimulant, occurs following administration of lisdexamfetamine to a patient. The controlled release has been reported to occur through hydrolysis of the amide bond linking D-amphetamine and L-lysine.
A procedure for making lisdexamfetamine hydrochloride is described in U.S. Pat. No. 7,223,735 to Mickle et al. (hereinafter Mickle). The procedure involves reacting D-amphetamine with (S)-2,5-dioxopyrrolidin-1-yl 2,6-bis(tert-butoxycarbonylamino)hexanoate to form a lysine-amphetamine intermediate bearing tert-butylcarbamate protecting groups. This intermediate is treated with hydrochloric acid to remove the tert-butylcarbamate protecting groups and provide lisdexamfetamine as its hydrochloride salt.
The procedure in Mickle for making lisdexamfetamine suffers several drawbacks that are particularly problematic when carrying out large scale reactions, such as manufacturing scale, to prepare lisdexamfetamine. For example, the process described by Mickle uses D-amphetamine as a starting material. D-amphetamine is a volatile liquid and vapor from the compound presents a health hazard to plant personnel involved with handling the compound. In addition, D-amphetamine is considered a schedule II controlled substance by the United States Drug Enforcement Agency. As such, the use of large quantities of this controlled substance requires special licenses, permits, and handling procedures and compliance with government regulatory provisions.
The amphetamine conjugate homoarginine-D-amphetamine has been described for use in the treatment of attention-deficit hyperactivity disorder. See, for example, International Patent Application No. WO 2008/073918. Similar to lisdexamfetamine, controlled release of D-amphetamine occurs following administration of homoarginine-D-amphetamine to a patient. Synthetic procedures for making homoarginine-D-amphetamine are described in International Patent Application No. WO 2008/073918, but the synthetic procedures use the schedule II controlled substance D-amphetamine.
Accordingly, the need exists for new methods and compositions for preparing amphetamine conjugates, such as lisdexamfetamine and homoarginine-D-amphetamine, and, in particular, preparing such compounds in high enantiomeric purity. The invention addresses this need and has other related advantages.